This invention pertains generally to the production of 17F and to the synthesis of 17F labeled fluoromethane and other fluoroalkanes and the use of such labeled materials in positron emission tomography.
Positron emission tomography (PET) has found wide application as a diagnostic method. Various radioisotopes have been investigated for application in PET and other diagnostic imaging methods. One of these radioisotopes is 15O 15O (txc2xd=122 seconds) tracers such as 15O labeled water are currently the most commonly used tracers in PET. One advantage of 15O labeled water as a tracer is that it can be easily and reliably synthesized. A disadvantage, however, is that it has a relatively low permeability surface product such that at high flows, the signal is reduced. Eichling et al. Circ. Res. 35, 358-364 (1974); Herscovitch et al. J. Cereb. Blood Flow Metab. 7, 527-542 (1987); Renkin, E. M. Am J. Physiol. 197, 1205-1210 (1959). Additionally, tracers such as 15O labeled water are usually administered by injection and are slow to clear test subjects.
Another radioisotope that has been used is 18F (txc2xd=110 minutes) in tracers such as 18F labeled fluoromethane which has been used to determine regional cerebral blood flow (rBCF). Gatley, et al. Int. J. Appl. Radiat. Isot. 32, 211-214, (1981). Because of the relatively long half life of 18F, tracers labeled with this isotope are ill suited for the fast repetitions necessary for cerebral activation protocols.
The short half life of 17F (Excex2+(max)=1.74 MeV; txc2xd≈64 seconds) suggests that this might be a suitable radioisotope for use in PET. The short half life presents problems, however, in that tracers labeled with this isotope must be prepared quickly in order to preserve the maximum amount of 17F in a labeled compound.
17F labeled fluoromethane has been prepared by several routes. For example, 17F labeled fluoromethane has reportedly been produced by Hunsdiecker like decomposition of 17F acetyl hypofluorite and by passage of 17F labeled F2 through CH3HgCl. Mulholland et al. J. Nuc. Med 28, 1082, (1987). These methods do not produce 17F labeled fluoromethane in sufficient yield for practical imaging use.
Therefore, a need exits for an improved method of generating 17F and for producing labeled fluoromethane and other fluoroalkanes from it. A need also remains for improved diagnostic methods using 17F labeled fluoromethane and other fluoroalkanes.
The present invention provides 17F labeled fluoromethane and other 17F labeled fluoroalkanes, and methods for producing 17F labeled fluoromethane and other 17F labeled fluoroalkanes. The invention also provides methods of determining the location of an 17F labeled tracer.
A method of generating 17F labeled fluoroalkanes includes contacting 17F labeled F2 with an alkane, preferably methane, a substituted or unsubstituted alkene, or a substituted or unsubstituted alkyne in the presence of a metal oxide catalyst to produce the 17F labeled fluoroalkane. In more preferred embodiments, the 17F labeled F2 is contacted with the alkane, the substituted or unsubstituted alkene, or the substituted or unsubstituted alkyne in the presence of the metal oxide catalyst and neon.
In preferred embodiments, the 17F is generated by proton irradiation of 20Ne in a target gas stream comprising neon, preferably natural neon gas. In still other embodiments, the target gas stream includes F2 and neon gas that includes 20Ne whereas in still other preferred embodiments, the target gas stream includes helium, F2, and neon gas that includes 20Ne.
In preferred embodiments, the 20Ne is irradiated with protons having an energy of greater than 8 MeV, more preferably with an energy of about 11 MeV. In another preferred embodiment the protons have an energy of about 16 MeV. The protons used to irradiate 20Ne are preferably generated by a cyclotron.
In another embodiment, the 17F is generated by deuteron irradiation of 16O in a target gas stream that includes O2.
In preferred processes, the target gas stream preferably comprises less than or about 1.0 percent, more preferably less than about 0.7 percent, and most preferably less than about 0.3 percent of F2. In still other preferred embodiments the total pressure of the target gas ranges from about 100 to about 400 psig or more preferably ranges from about 160 to about 240 psig.
In other preferred embodiments of producing 17F labeled fluoromethane, the 17F labeled F2 is contacted with methane, and the metal oxide catalyst is silver oxide, preferably at a temperature ranging from about 200xc2x0 C. to about 600xc2x0 C. More preferably, the metal oxide is at a temperature ranging from about 400xc2x0 C. to about 500xc2x0 C., and most preferably the metal oxide is at a temperature of about 450xc2x0 C.
In other more preferred embodiments of producing 17F labeled fluoroalkanes, the 17F labeled F2 is contacted with the substituted or unsubstituted alkene or the substituted or unsubstituted alkyne and the metal oxide catalyst is silver oxide which is more preferably at a temperature ranging from about 10xc2x0 C. to about 600xc2x0 C. or still more preferably is at a temperature ranging from about 20xc2x0 C. to about 100xc2x0 C. Most preferably, the metal oxide catalyst is at a temperature of about 25xc2x0 C. in the process for producing 17F labeled fluoroalkanes.
In still other preferred embodiments, the alkene or alkyne contacted with the 17F labeled F2 is a haloalkene or haloalkyne, more preferably a fluorinated alkene or alkyne. Still more preferably, the alkene is a difluoroalkene, yet more preferably 1,1-difluoroethylene such that the 17F labeled fluoroalkane produced is 17F labeled 1,1,1,2-tetrafluoroethane where one of the fluorine atoms is an 17F fluorine atom.
In still other preferred embodiments, the 17F labeled fluoroalkane is passed through a scrubber, preferably a soda lime scrubber.
In yet other preferred embodiments of the method of generating the 17F labeled fluoroalkane, the 17F is continuously generated by continuously irradiating the target gas stream with protons and the 17F labeled fluoroalkane is continuously produced by continuously contacting the 17F labeled F2 with the alkane, the substituted or unsubstituted alkene, or the substituted or unsubstituted alkyne, more preferably methane.
A method of determining the location of an 17F labeled tracer is also provided. The method includes generating the 17F labeled fluoroalkane according to the invention; administering the 17F labeled fluoroalkane to a test subject; and collecting scans of the test subject using a radiosensitive detector. In preferred such methods, the 17F labeled fluoroalkane is administered to the test subject by having the test subject inhale the 17F labeled fluoroalkane. In another preferred method of determining the location of an 17F labeled tracer, the 17F labeled fluoroalkane is added to a saline solution and the saline solution is administered to the test subject.
Preferred radiosensitive detectors for use in determining the location of an 17F labeled tracer such as 17F labeled fluoromethane and other 17F labeled fluoroalkanes, are selected from a scintillation detector, a Geiger counter, a positron emission tomography scanner, a single photon emission computed tomography scanner, or a solid state detector. More preferred radiosensitive detectors for use in the method of determining the location of an 17F labeled tracer are positron emission tomography scanners or cameras.
In other more preferred embodiments of producing 17F labeled fluoroalkanes, the 17F labeled F2 is contacted with the substituted or unsubstituted alkene or the substituted or unsubstituted alkyne and the metal oxide catalyst is silver oxide which is more preferably at a temperature ranging from about 10xc2x0 C. to about 600xc2x0 C. or still more preferably is at a temperature ranging from about 20xc2x0 C. to about 100xc2x0 C. Most preferably, the metal oxide catalyst is at a temperature of about 25xc2x0 C. in the process for producing 17F labeled fluoroalkanes.
In still other preferred embodiments, the alkene or alkyne contacted with the 17F labeled F2 is a haloalkene or haloalkyne, more preferably a fluorinated alkene or alkyne. Still more preferably, the alkene is a difluoroalkene, yet more preferably 1,1-difluoroethylene such that the 17F labeled fluoroalkane produced is 17F labeled 1,1,1,2-tetrafluoroethane where one of the fluorine atoms is an 17F fluorine atom.
The invention also provides the 17F labeled fluoromethane and fluoroalkanes produced by the processes of the invention.
17F labeled organic compounds are provided and include 17F labeled fluoromethane and an 17F labeled alkane having more than 2 carbon atoms. In more preferred 17F labeled organic compounds, the alkane comprises at least two fluorine atoms and at least one of the fluorine atoms is an 17F. In still other more preferred 17F labeled organic compounds, the 17F labeled alkane is 1,1,1,2-tetrafluoroethane where at least one of the F atoms is an 17F fluorine atom.
The invention still further provides gaseous compositions that include 17F labeled fluoromethane that has an equilibrium activity of greater than or about 20 mCi. In some preferred embodiments, the equilibrium activity level is greater than or about 40 mCi whereas in still other preferred embodiments, the equilibrium activity level is greater than or about 70 mCi.
Further objects, features and advantages of the invention will be apparent from the following detailed description when taken in conjunction with the accompanying drawings.